Sex-biased TGFβ signalling in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare cardiovascular disorder leading to pulmonary hypertension and, often fatal, right heart failure. Sex differences in PAH are evident, which primarily presents with a female predominance and increased male severity. Disturbed signalling of the transforming growth factor-β (TGFβ) family and gene mutations in the bone morphogenetic protein receptor 2 (BMPR2) are risk factors for PAH development, but how sex-specific cues affect the TGFβ family signalling in PAH remains poorly understood. In this review, we aim to explore the sex bias in PAH by examining sex differences in the TGFβ signalling family through mechanistical and translational evidence. Sex hormones including oestrogens, progestogens, and androgens, can determine the expression of receptors (including BMPR2), ligands, and soluble antagonists within the TGFβ family in a tissue-specific manner. Furthermore, sex-related genetic processes, i.e. Y-chromosome expression and X-chromosome inactivation, can influence the TGFβ signalling family at multiple levels. Given the clinical and mechanistical similarities, we expect that the conclusions arising from this review may apply also to hereditary haemorrhagic telangiectasia (HHT), a rare vascular disorder affecting the TGFβ signalling family pathway. In summary, we anticipate that investigating the TGFβ signalling family in a sex-specific manner will contribute to further understand the underlying processes leading to PAH and likely HHT.